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Biomedical subjects

H M Frost

Publications and source records attributed to H M Frost.

At least 19 recordsLinked to original sources
PubMed2004

Coming changes in accepted wisdom about "osteoporosis".

Here a voice from the past suggests 28 changes that will affect how people study, manage, classify and think about "osteoporoses" today. Those changes depend mainly on two things: (i) "Connecting the dots" between diverse evidence and ideas from many fields and sources in order to find larger "messages" hidden in mountains of often poorly-organized lesser details, (ii) and features of the still-evolving Utah paradigm of skeletal physiology. That paradigm sums contributions from many people who worked in many fields for over 100 years. In one view it is the most important development in skeletal physiology since Rudolf Virchow and others realized approximately 150 years ago that cells provide the basis for human physiology and diseases. This article emphasizes the above messages instead of the details. The messages affect ideas about the nature, pathogenesis, diagnosis, classification, study and management of osteopenias and osteoporoses, as well as some roles of muscle, drugs, hormones, other agents and fatigue damage, in those disorders. Those larger messages also concern how to classify "osteoporosis fractures", how to define bone health, the choice of absorptiometric methods for noninvasive evaluations of bones, osteopenias and muscle strength, and new criteria for selecting patient cohorts for "risk-of-fracture" analyses and in searches for genetic roles in "osteoporoses". Finally, those larger messages identify many new targets for research that should prove unusually useful in clinical and pharmaceutical domains and work.

Absorptiometry, Photon↗
PubMed2003

New targets for fascial, ligament and tendon research: a perspective from the Utah paradigm of skeletal physiology.

Here an octogenarian voice from the past argues that the physiology of fascia, ligaments and tendons has strong and useful analogs in some general features of bone physiology, including the latter's tissue-level mechanostat. Such analogs could provide unusually important targets for future collagenous-tissue research. Even by 2002, this field's authorities seldom discussed those analogs so this text concerns them. How well the above research proceeds could depend partly on A) making collagenous- tissue physiologists aware of those analogs (hence this article), B) on following a four-step analytical strategy, C) on "connecting the dots" between evidence and ideas from many clinical and basic-science fields to find larger "messages" and patterns hidden in mountains of lesser things, D) and on combining (i), cell- and molecular-biologic work, expertise and insights, (ii) with live-animal research and expertise and insights of the Utah paradigm of skeletal physiology. Why the "in vitro/in vivo collaboration" in "D" above? Partly because few, if any, skeletal tissue-level mechanisms function normally in current cell, tissue and organ culture systems. Consequently and historically an agent's in vitro effects seldom predicted correctly its in vivo effects, although the former effects may help to explain the latter ones after other studies revealed the latter ones. Things summarized in this article provide a foundation on which to build in the future. Since aging and other things took me out of that "building game", younger people will do that building when and how, and if, they wish to. The directions for that building suggested in this article differ enough from currently accepted "wisdom" that it may take years for most physiologists to concede their merit and begin that building in earnest. If so, so be it.

Journal Article↗
PubMed2003

Perspective: genetic and hormonal roles in bone disorders: insights of an updated bone physiology.

In 1997 Professor J. Gorski suggested endocrinology needed new paradigms (Endocrine News 1997; 22:4,12). 'Connecting the dots' between diverse facts and ideas drawn from many lines of inquiry, plus accumulating evidence and increasing inadequacies of earlier ideas and terminology, led to an updated bone physiology called the 'Utah paradigm' that reveals new genetic and hormonal potential roles in bone physiology and disorders. One way to find a bone disorder's cause(s) and treatment( s) could depend on understanding the underlying physiology well enough to design effective drugs for it. In early views cell-level effects on osteoblasts and osteoclasts could explain most endocrine and genetic roles in bone disorders. The updated bone physiology supplements those views with roles of bone's tissue-level 'nephron-equivalent' mechanisms (NEMs) and their functions (NEFs), including some roles of biomechanics, whole-bone strength and muscle strength. That updated physiology reveals at least 42 nexuses above the cell level, some of them extraosseous, where genetic and/or hormonal effects might cause or help to treat varied bone problems. That multifactorial physiology also suggests that in vivo skeletal phenomena usually depend on many interlocking, laddered and nested feedback systems. Due to lack of study, how genes and hormones affect those nexuses and feedback systems still remains nearly unknown. Because studies of bone physiology in in vitro systems seldom if ever correctly predicted the in vivo effects, further live-animal research should seek the in vivo effects. This article suggests why more of that kind of research is needed, and some directions it could take.

Journal Article↗
PubMed2003

On the strength-safety factor (SSF) for load-bearing skeletal organs.

The strength of healthy postnatal mammalian load-bearing bones, growth plates, joints, fascia, ligaments and tendons exceeds the minimum strength needed to keep voluntary mechanical usage from breaking or rupturing them or from causing arthroses. Thus, they have a strength-safety factor (SSF). Some general features of the physiology in the Utah paradigm of skeletal physiology can explain two things: (i) Why load-bearing bones should have an SSF, (ii) and why its numerical value should approximately 6 in healthy young adult mammals. The number and kinds of studies and facts that revealed those two things for load-bearing bones do not yet exist for the extraosseous load-bearing organs that are made with cartilage and collagenous tissue. However, clinical-pathologic observations suggest the latter organs' SSFs should depend on features analogous to those that create SSFs for load-bearing bones. If so, the physiology on which bone's SSF depends could suggest directions for future studies of the SSF determinants of load-bearing extraosseous organs. Biomechanicians currently favor strain above stress when discussing biomechanical roles in the functional adaptations of bones to mechanical loading. However, an SSF is best expressed in stress terms, so a Table in this article provides corresponding strain/stress/unit-load values for bone's three important thresholds, and for its ultimate strength.

Journal Article↗
PubMed2003

On the pathogenesis of osteogenesis imperfecta: some insights of the Utah paradigm of skeletal physiology.

The pathogenesis of osteogenesis imperfecta (OI) baffled physiologists and physicians for over a century. Most past efforts to explain it depended heavily on cell and molecular biology and on changes in the material properties of affected bones (an old idea that OI patients could not make enough bone erred). To such views the still-evolving Utah paradigm of skeletal physiology can add a model for bone and bones that depends on errors in three genetically-determined features. The errors include, 1,2) elevated 'set points' of the strain-dependent thresholds that help to control how lamellar bone modeling and remodeling adapt bone strength, architecture and 'mass' to the voluntary loads on load-bearing bones; 3) and a reduced modeling-rate limit for the appositional rate of the lamellar bone formation drifts that can increase bone strength, outside bone diameters, cortical and trabecular thickness, and bone 'mass'. If only abnormalities #1,#2 occurred, that should limit the eventual strength, architecture and 'mass' of load-bearing bones, while if only #3 occurred that should prolong or delay how long it took to achieve the above limits, but without changing them. Equally, in driving from New York to Boston, stopping at New Haven would prevent reaching Boston no matter how rapidly one drove (a limited trip). But by not stopping one could reach Boston by driving very slowly (a prolonged but not a limited trip). This model concerns general features of bone and bones in OI that would need study and explanation at the tissue, cellular and molecular-biologic levels. Other places and people must discuss any devils in the details, as well as collagenous tissue, auditory, dental and other problems in OI, and the effects of treatment on the above features.

Journal Article↗
PubMed2001

From Wolff's law to the Utah paradigm: insights about bone physiology and its clinical applications.

Efforts to understand our anatomy and physiology can involve four often overlapping phases. We study what occurs, then how, then ask why, and then seek clinical applications. In that regard, in 1960 views, bone's effector cells (osteoblasts and osteoclasts) worked chiefly to maintain homeostasis under the control of nonmechanical agents, and that physiology had little to do with anatomy, biomechanics, tissue-level things, muscle, and other clinical applications. But it seems later-discovered tissue-level mechanisms and functions (including biomechanical ones, plus muscle) are the true key players in bone physiology, and homeostasis ranks below the mechanical functions. Adding that information to earlier views led to the Utah paradigm of skeletal physiology that combines varied anatomical, clinical, pathological, and basic science evidence and ideas. While it explains in a general way how strong muscles make strong bones and chronically weak muscles make weak ones, and while many anatomists know about the physiology that fact depends on, poor interdisciplinary communication left people in many other specialties unaware of it and its applications. Those applications concern 1.) healing of fractures, osteotomies, and arthrodeses; 2.) criteria that distinguish mechanically competent from incompetent bones; 3.) design criteria that should let load-bearing implants endure; 4.) how to increase bone strength during growth, and how to maintain it afterwards on earth and in microgravity situations in space; 5.) how and why healthy women only lose bone next to marrow during menopause; 6.) why normal bone functions can cause osteopenias; 7.) why whole-bone strength and bone health are different matters; 8.) why falls can cause metaphyseal and diaphyseal fractures of the radius in children, but mainly metaphyseal fractures of that bone in aged adults; 9.) which methods could best evaluate whole-bone strength, "osteopenias" and "osteoporoses"; 10.) and why most "osteoporoses" should not have bone-genetic causes and some could have extraosseous genetic causes. Clinical specialties that currently require this information include orthopaedics, endocrinology, radiology, rheumatology, pediatrics, neurology, nutrition, dentistry, and physical, space and sports medicine. Basic science specialties include absorptiometry, anatomy, anthropology, biochemistry, biomechanics, biophysics, genetics, histology, pathology, pharmacology, and cell and molecular biology. This article reviews our present general understanding of this new bone physiology and some of its clinical applications and implications. It must leave to other times, places, and people the resolution of questions about that new physiology, and to understand the many devils that should lie in its details. (Thompson D'Arcy, 1917).

Adult↗
PubMed2001

Bipedal stance exercise enhances antiresorption effects of estrogen and counteracts its inhibitory effect on bone formation in sham and ovariectomized rats.

In this study we employed a raised cage model in combination with estrogen to observe their effects on the proximal tibial metaphysis (PTM) and tibial shaft (TX) in sham-operated or ovariectomized rats. A total of 105 6-month-old female Sprague-Dawley rats were used in the study. Bilateral sham ovariectomy or ovariectomy was performed at day 0 and the rats were housed in normal height or raised cages (RCs) and injected subcutaneously twice per week with 10 microg/kg of 17beta-estradiol (E2) or vehicle for 4 and 8 weeks. Because the time course of bone loss or bone gain distribution was not uniform in the metaphyses of the tibia, we subdivided the PTM into three zones (medial, central, and lateral) to observe the different bone loss or bone gain patterns after ovariectomy and/or raised cages. We found that: (1) E2 alone did not alter bone area or architecture in sham rats, whereas RC alone increased trabecular thickness and area of PTM, but had no effects on TX; (2) Ovx induced most bone loss from the central zone of the PTM and endocortical surface of TX, accompanied by decreased trabecular number and increased bone resorption; (3) E2 alone prevented ovx-induced bone loss by preserving trabecular number and depressing bone resorption; (4) RC alone partially compensated for bone loss following ovx by thickening the surviving trabeculae in lateral and medial zones, and tended to stimulate bone formation and decrease bone resorption; and (5) RC plus E2 increased trabecular bone area by having an additive effect on bone resorption and bone turnover. RCs helped to prevent the depressive effect of estrogen on periosteal bone formation. In conclusion, early and rapid bone loss occurred in the central zone of the metaphysis and endocortical surface after ovx. Estrogen replacement therapy prevented this loss. Raised cages partially compensated for bone loss following ovx by thickening the trabeculae in the lateral area of the metaphysis and decreased endocortical erosion. Combination treatment added bone to the PTM and prevented the decrease of periosteal bone formation after estrogen administration.

Animals↗
PubMed2001

Seeking genetic causes of "osteoporosis:" insights of the Utah paradigm of skeletal physiology.

This article investigates: (1) the criteria used to select cohorts of patients for study when seeking genetic causes of "osteoporosis;" (2) the possibilities, genetic and otherwise, that might cause or help to cause this disorder; and (3) how one should define this disorder and bone health. Patients selected for such a study because current World Health Organization (WHO) absorptiometric criteria diagnosed them with "osteoporosis," or because they had extremity bone fractures, could possibly include people with biologically different disorders, in addition to those with healthy or diseased bones. Seeking a common genetic cause of "osteoporosis" in such inhomogeneous cohorts may be like seeking a common genetic cause of "anemia" in a cohort that contained iron deficiency and pernicious anemias, thalassemia, sickle-cell disease, anemias due to blood loss, malnutrition, malaria, metastatic disease, etc. The Utah paradigm's insights suggest how to select more homogeneous cohorts for such studies. This would require defining bone health in a way that acknowledges the main purpose of load-bearing bones, which the WHO criteria do not do. The present understanding of bone physiology indicates that many biologic mechanisms and features could cause or help to cause an osteopenia or osteoporosis. This study identifies 30 such mechanisms, some osseous and some extraosseous, and even this number seems conservative. Because each such mechanism could depend on any number of genes, when a strong genetic association with some kind of osteopenia or osteoporosis is found it could be difficult to determine which mechanism(s) it perturbed. This article summarizes the evidence and ideas on which these suggestions depend.

Bone Remodeling↗
PubMed2001

Does bone mass equate with bone health? An argument for the negative.

This article argues that diagnosing osteopenias and osteoporoses by bone mass Z-scores, and viewing disorders detected in that way as diseases, fostered a belief that those scores evaluate whole-bone strength and bone health equally well (here, mass has its meaning in absorptiometry, not in physics). However, load-bearing bones normally adapt their strength to the past and present voluntary loads on them in ways that make strong muscles make strong bones, and make persistently weak muscles make weak bones. The resulting adaptations also make bones strong enough to keep voluntary mechanical usage from fracturing them. Such observations suggest a new criterion for a bone's health that would depend on the relationship among its strength, the size of the voluntary loads it carries, and any spontaneous fractures caused by those loads. Such a relationship could indicate a bone"s health independently of its mass. For example, mouse and horse femurs differ in strength more than 1000-fold, but they could be equally healthy if they were to satisfy that criterion in the animals from which they come. That idea would distinguish abnormal in a strictly statistical sense (which T- and Z-scores would evaluate) from unhealthy in the sense of both abnormal and diseased (which the above relationship would evaluate). Thus, a bone with a negative Z-score could still be healthy if voluntary loads do not fracture it. These ideas and some of their implications question some long-held views. This article presents the ideas, evidence they stand on, and some of their implications.

Absorptiometry, Photon↗
PubMed2001

Should future risk-of-fracture analyses include another major risk factor? The case for falls.

This article proposes two things. (i) The major risk of so-called osteoporotic fractures that affect extremity bones (hips, wrists, etc.) consists of falls. Impairments of balance, vision, muscle strength, and neuromuscular coordination increase falls in aging adults, and when an osteopenia coexists, that makes such fractures more likely than otherwise. (ii.) Risk-of-fracture studies should separate patients who develop fractures from falls or injuries, from patients in whom fractures occur spontaneously, meaning during ordinary voluntary physical activities instead of from any kind of trauma.

Accidental Falls↗
PubMed2001

On longitudinal bone growth, short stature, and related matters: insights about cartilage physiology from the Utah paradigm.

Precursor cell division in growing cartilage determines human height, the lengths of the spine and limb bones, the alignment of joints, spines and limbs, and the ratio of spinal length to limb length. That division also helps to determine the sizes and shapes of joints, apophyses and epiphyses. Ideas about what controls those facts are changing. To former views, in which mainly genetic and humoral factors controlled them, the Utah paradigm of skeletal physiology adds long-overlooked biomechanical including muscular factors. These three kinds of factors would collaborate in controlling the precursor cell division that determines the above skeletal features. Problems with that control clearly cause or help to cause many clinical disorders. Examples include short stature, gigantism, premature and delayed skeletal maturation, some changes in fracture patterns associated with puberty, joint malalignments, congenital hip dysplasia, scoliosis, limb torsions, the ball-and-socket ankle, and some skeletal abnormalities in Marfan's syndrome and the osteochondrodystrophies. The physiology such things depend on has matured sufficiently to justify a review for pediatricians, endocrinologists and other clinical specialists, and many basic scientists.

Animals↗
PubMed2001

Why should many skeletal scientists and clinicians learn the Utah paradigm of skeletal physiology?

Adding later facts and ideas to a universally accepted "1960 paradigm" of skeletal physiology led to the still-evolving "Utah paradigm". The ASBMR's William Neuman award in 2001 to one of the latter paradigm's architects (HMF) suggested that physiologists began to view it as a valid supplement to its predecessor. Nevertheless it diffused poorly among most SSCs (Skeletal Scientists and Clinicians, plus all others who work in any way on skeletal matters), even though success in the quest for knowledge and recognition by many of them could depend on learning that paradigm's insights. Those insights can help to minimize serious errors in some experimental designs and in interpreting some kinds of data. To explain how success in that quest could depend on the Utah paradigm requires explaining the nature of the above errors, some features of both paradigms, some implications of the newer one, and when that quest's success might not require knowing the Utah paradigm. A three-part message distilled from the past for present and future SSCs concludes the article. It took decades to understand such things and find effective ways to explain them, and both matters probably need improvement (to paraphrase Pogo, "We met the enemy and perhaps it was us more than them"). During those decades the author changed from an active SSC hunter-player to a spectator, known to some as a feisty eccentric old dinosaur (FEOD) (Note A). So here a voice from the past would speak to present and future SSCs.

Journal Article↗
PubMed2001

Does the anterior cruciate have a modeling threshold? A case for the affirmative.

Growing evidence supports a 1972 proposal that dynamic tension strains of a ligament above a threshold range, but below its ultimate strength, would make its cells synthesize more collagen to thicken and strengthen it. If so, when that strengthening reduced later strains to the bottom of that threshold range this "diametric modeling" would stop. A) Such a mechanism must create a "strength-safety factor" that would minimize or prevent voluntary activities from rupturing healthy ligaments, so chiefly injuries would rupture them. B) Such a mechanism should also make the usual largest loads on a healthy anterior cruciate ligament (ACL) determine its strength, and would make smaller loads mixed with large ones have little effect on its strength. C) In principle, when an ACL's strains exceeded that threshold range, diametric modeling would turn on, strengthen it, and reduce subsequent strains from the same loads. When its strains remained smaller, this mechanically-controlled modeling would turn off. Normal ACLs do have a strength-safety factor so they could have a diametric modeling threshold too, as we now know bone does. In healthy young adult humans available evidence suggests that threshold's value could lie in the region of 23 Newtons/mmC of the ACL's cross section area. If similar relationships applied to fascia, tendons and other ligaments (I suggest they do), they would form fundamental biomechanical properties of collagenous tissue organs.

Journal Article↗
PubMed2001

The Utah paradigm on animal models of skeletal disorders: quo vadis?

Skeletal disorders that need effective studies in suitable animal models include "osteoporosis", arthroses and hard and soft tissue healing. For people doing or analyzing such studies this article provides a brief overview and some salient implications of the Utah paradigm of skeletal physiology. The article leaves discussing and resolving any disagreements and controversies about such things to other times, places and people.

Journal Article↗
PubMed2001

A novel method to 'exercise' rats: making rats rise to erect bipedal stance for feeding - raised cage model.

We employed a novel method to exercise rats: making them rise to bipedal stance for feeding using raised cages. We studied its effects on the skeletons of 6 and 10-month-old intact or orchidectomized (ORX) rats. Body and hindlimb muscle weights, tibial BMC and periosteal cortical bone formation increased after housing in raised cages, but more so in 6-month-old animals than in 10-month-old ones. In 6-month-old orchidectomized rats, raised cages partially prevented ORX-induced bone loss by stimulating periosteal cortical bone (TX) formation and decreased bone resorption next to marrow. In 10-month-old male orchidectomized rats, raised cages also decreased the endosteal and trabecular bone resorption, but not enough to prevent completely ORX-induced net bone losses. Because the osteogenic effects of raised cages alone were only partial, we also studied the interaction between raised cage and prostaglandin E(2) (PGE(2)) in 10-month-old retired female breeders. When treated with combined raised cage and PGE(2), both cortical (TX) and trabecular bone mass of the proximal tibial metaphysis and lumbar vertebral body increased over either raised cages or PGE(2) treatment alone, that was accompanied by dramatic increased bone formation at periosteal and endosteal surfaces. Thus making rats rise to erect bipedal stance for feeding helps to prevent bone loss after orchidectomy; it amplifies the anabolic effects of PGE(2), and it provides an inexpensive, non-invasive and reliable way to increase mechanical loading of certain bones of the rat skeleton.

Journal Article↗